Method for the medicinal prophylaxis of cholinesterase inhibitor intoxication, and active substances and medicaments suitable therefor

ABSTRACT

(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (formula (1)) or at least one active ingredient according to formula (2) for the preventive protection of people from poisoning caused by cholinesterase inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application of InternationalApplication No. PCT/EP2004/000289, filed on Jan. 16, 2004, which claimspriority of German application number 103 01 851.4, filed on Jan. 17,2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods for the drug prophylaxis ofpoisoning caused by cholinesterase inhibitors, in particular those fromthe class of organophosphorus compounds. The present invention furtherrelates to active ingredients and medicaments which are suitable asprophylactic agents/compositions for such poisoning, particularlymedicaments containing active ingredients from the group of the phenylcarbamates. The invention further encompasses the use of the activeingredients for the prophylaxis of the poisoning.

2. Description of the Prior Art

Compounds with a cholinesterase-inhibiting effect are employed on theone hand as insecticides and fungicides in crop protection, and on theother hand some of these compounds are suitable for use as combat agentsor combat gases in wars or in terrorist attacks. While in the lattercase the toxic effect is intended, the poisoning of people caused byinsecticides or fungicides is attributable to improper handling,especially inadequate safety measures during transport or during use.

The risk of being exposed to a poison gas attack has increased againrecently because of terrorist activities. An additional factor is thatsome countries are producing or storing combat gases and are consideringthe use of such weapons to achieve their military aims. Those at riskare not only soldiers on combat operations but increasingly also thecivil population and, in particular, the rescue services.

Nerve combat agents or nerve gases from the class of organic phosphoricacid esters and phosphonic acid esters are the most frequently usedpoison gases. The principal representatives of these combat agents aretabun (GA), sarin (GB), soman (GD), and VX.

Examples of representatives which may be mentioned of organophosphateshaving pesticidal or fungicidal activity and used in agriculture orhorticulture are parathion (diethyl (4-nitrophenyl) thionophosphate),dimethoate (dimethyl S-methylcarbamoylmethyl dithiophosphate) andmalathion.

The toxic effect of these combat agents, as well as that of theorganophosphates and carbamates used as insecticides or fungicides,derives from inhibition of cholinesterase, resulting in an excessiveaccumulation of the neurotransmitter acetylcholine at the cholinergicreceptors. The excessive activation of peripheral and central receptorscauses severe paralytic symptoms, with death usually being caused by therespiratory paralysis which occurs. Further clinical symptoms are, forexample, hypersalivation, apnoea and fits; these symptoms occur withinthe first few minutes after exposure to combat agents. If these symptomsare not treated adequately and immediately, they can cause death orpermanent damage, comparable to the consequences of irreversible braindamage.

The antidote normally administered for the therapy of acuteorganophosphate poisoning is atropine in high parenteral doses in orderto antagonize the effect of acetylcholine. This can take place with theaid of so-called autoinjectives which are intended to make it possiblefor the affected people in an emergency to self-administer the necessaryatropine dose. However, such a treatment promises success only if it isundertaken, at the latest, within one minute after intake of the poison.In actual circumstances, this is possible in very rare cases because thetime available in an emergency (e.g. in combat operations or terroristattacks) is too short. This applies in particular to the extremelypoisonous combat agents sarin (GB) and soman (GD). In addition, theatropine dose employed for the treatment must be carefully selecteddepending on the severity of the poisoning in order to avoid overdosageand atropine poisoning. In practice this is realistically hardlypossible under the circumstances existing in the said operations.

It is possible in some cases to treat an organophosphate poisoning byadministering oxime compounds (e.g. obidoxime, pralidoxime). However,oximes are effective only for certain alkyl phosphates (e.g. parathion),and the treatment must be undertaken as soon as possible after exposureto the poison. Oximes are effective for most organophosphates except forsoman (GD), for example.

Only inadequate preventive means are available for the poisoningmentioned. One known example is oral administration of pyridostigmine,which was carried out in the second Gulf war as a measure to protect thesoldiers from exposure to poison gas. However, this treatment has nowbeen abandoned because pyridostigmine is suspected of causing seriousside effects partly responsible for the Gulf War Syndrome. The compoundpyridostigmine as such does not exhibit independent protective action.In the above-mentioned case, pyridostigmine was used only aspretreatment, not as a prophylactic agent. The intention of thispretreatment is to improve the actual treatment with the second activeagent, the antidote atropine.

A further reason why pyridostigmine is no longer used is that to datethere is no regular approval based on extensive clinical experimentsproving the harmlessness of this medicament.

Furthermore, the currently available antidote therapies do not offeradequate protection from paroxysms caused by exposure to nerve gas, andfrom the long-term cerebral damage and cognitive disorders resultingtherefrom.

DE 43 42 173 A1 proposed a combination of physostigmine and scopolamineas a prophylactic measure or for pre-treatment of organophosphatepoisoning, the intention being to administer this combination by meansof injection or skin plaster. However, it is a disadvantage thatphysostigmine is not approved as medicament. There are thus justifiedworries that physostigmine might, because of its chemical similarity topyridostigmine, cause similar side effects as the latter.

SUMMARY OF THE INVENTION

The object of the present invention is to indicate methods forprophylaxis of poisoning by cholinesterase inhibitors, and medicamentssuitable for this purpose, it being intended to avoid or reduce theaforementioned disadvantages of known methods and medicaments.

DETAILED DESCRIPTION OF THE INVENTION

In animal experiments (see the example) it has emerged, surprisingly,that this object is achieved by using(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate(“compound (1)”) as prophylactic agent.

The solution according to the invention therefore encompasses methodsfor prophylactic treatment of poisoning caused by cholinesteraseinhibitors, said methods being based on administration of(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate or of amedicament containing said active ingredient. The invention furtherrelates to the use of(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate or of amedicament containing said active ingredient for the prophylaxis ofpoisoning caused by cholinesterase inhibitors. The invention furthermoreencompasses medicaments containing the active ingredient(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate incombination with at least one further pharmaceutical active ingredient.

Compound (1) is a carbamic acid ester which inhibits the enzymecholinesterase by carbamylation. This inhibition is reversible with ahalf-life of a few minutes. Because of these properties, this activeagent is employed for the therapy of Alzheimer's disease, the intentionin this case being to compensate for the acetylcholine deficit caused bythe destruction of cholinergic neurons. Compound (1) is approved asmedicament for the treatment of Alzheimer's disease and is on themarket; it causes an improvement in memory performance at least in somepatients. The medicament is regarded as safe; no serious side effectsare known. A further advantage is that(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate isabsorbed well from the gastrointestinal tract and easily crosses theblood-brain barrier.

The use of (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenylcarbamate as a safe prophylactic for the prophylaxis of poisoning bycholinesterase inhibitors, especially organophosphate poisoning, haspreviously not been known. This specific particularly good suitabilityhas surprisingly emerged in animal experiments. In these experiments ithas emerged as a particular advantage that obviously a considerablylower dose is needed than in the normal therapy of Alzheimer's disease.

The medicaments of the invention for prophylactic treatment oforganophosphate poisoning contain the active agent(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate as afree base or in the form of a pharmaceutically acceptable acid additionsalt. Particularly suitable salts are: salicylate, hydrogen tartrate,hydrobromide and hydrochloride. Particularly suitable is the hydrogentartrate salt of the active agent (molecular formula C₁₄H₂₂N₂O₂·C₄H₆O₆),with the tartaric acid preferably being present in the configuration(2R, 3R).

The free active substance base or the acid addition salts thereof may beused as racemic mixtures; the (−)-enantiomer of(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate and itsacid addition salts are, however, preferred because of their greaterselectivity. If the active ingredient is present in the form of an acidaddition salt, the direction of rotation may be (+) or (−).

The free base (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenylcarbamate can be obtained by amidation of□-m-hydroxyphenylethyl-dimethylamine with a corresponding carbamoylhalogenide. The separation of the racemates and the preparation of theacid addition salts may be accomplished according to known methods. Theracemic mixture of the hydrochloride form of compound (1) is known fromEP-A-0 193 926 (where it is designated as “RA₇HCl”). The (−)-enantiomerof compound (1) and its acid addition salts are described in DE 38 05744 A1.

Suitable as active ingredients which according to the present inventionmay be utilized for the prophylactic treatment of poisoning caused bycholinesterase inhibitors are furthermore the compounds of the generalstructural formula (2):

In this formula the residue R₁ is selected from the group consisting ofhydrogen, straight-chain and branched lower alkyl residues (1 to 5 Catoms), cyclohexyl, allyl and benzyl; the residue R₂ is selected fromthe group consisting of hydrogen, methyl, ethyl and propyl; the residueR₃ is selected from the group consisting of hydrogen as well asstraight-chain and branched lower alkyl residues (1 to 5 C atoms); theresidues R₄ and R₅ are selected from the group of the straight-chain andbranched lower alkyl residues (1 to 5 C atoms), with R₄ and R₅ beingidentical or different; the dialkylaminoalkyl group with the residuesR₃, R₄ and R₅ can optionally be in ortho, meta or para position.

The active agent compounds according to formula (2) may be used as freebases or in the form of their pharmaceutically acceptable acid additionsalts. The salts mentioned in connection with compound (1), particularlythe hydrogen tartrate and the hydrochloride, are particularly suitable.

Compounds of the formula (2) and their production are disclosed inEP-A-0 193 926.

According to one embodiment of the invention, the compound (1) or one ofthe compounds according to formula (2), each, where appropriate, in theform of a pharmaceutically acceptable salt, is administered as the soleactive agent for the prophylaxis of poisoning caused by cholinesteraseinhibitors to persons who are at risk. This is a prophylactic measurewhich by itself is sufficient and does not necessitate any furthertherapeutic measures or active agents.

Another embodiment provides for the compound (1) or one of the compoundsaccording to formula (2), each, where appropriate, in the form of apharmaceutically acceptable salt, in combination (i.e. simultaneously orconsecutively in time) with one or more additional active ingredient(s),to the person to be treated. This or these active ingredient(s) areselected from the group of the parasympatholytics, such as from thegroup of the tropane alkaloids, namely scopolamine. Further suitableactive ingredients from this group are: atropine, butylscopolamine,benzatropine. These active ingredients may also be present in the formof their pharmaceutically acceptable salts.

The combination of compound (1) or of an active ingredient according toformula (2) with at least one active ingredient from the group of theparasympatholytics, in particular from the group of tropane alkaloids,may be employed because these active ingredients are competitiveantagonists of released acetylcholine and thus reduce the unwantedeffects caused by the cholinesterase-inhibitory effect of compound (1).

The present invention also encompasses medicaments with a content ofcompound (1) or of an active ingredient according to formula (2), whereappropriate in the form of a pharmaceutically acceptable salt. Thisincludes medicaments of the invention which contain such a phenylcarbamate active ingredient as the sole active ingredient component.

The medicament employed for prophylaxis may contain one or moreadditional active ingredient(s), as described above, said activeingredient(s) being selected from the group of the parasympatholytics.

The medicaments of the invention which contain compound (1) or at leastone compound according to formula (2) can be produced using knownadjuvants in various types of dosage forms. Pharmaceutical forms forenteral or for parenteral, particularly transdermal administration areemployed in the prophylactic methods according to the invention. In theformer case, the active ingredient(s) is/are present in an oral enteraldosage form (e.g. tablet, coated tablet, chewable tablet, suckabletablet, capsule, powder, suspension, solution) or in a rectal dosageform (e.g. suppository). Suitable formulation adjuvants are known to theskilled person.

Also suitable are parenteral oral administration forms such as suckabletablets, sublingual tablets, sheet-like adhesive systems applied to theoral mucosa, sheet-like systems that disintegrate on the tongue or inthe oral cavity and administer the active agent by adhering to the oralmucosa.

Furthermore, devices for administering medicaments to mucosal tissue, asdescribed in DE 0069030095 T2 and DE 0069032982 T2, are also suitable.These devices can be used like lollipops and substantially comprise acarrier device which is attached to a total mass.

Application by means of the “Methods and apparatus for using controlledheat to regulate transdermal delivery” described in US-A 2001037104(Zhang Jie et al.) is also suitable.

The medicaments of the invention can, however, also be formulated asinjection solutions and be present, for example, inside a disposablesyringe. Depot pharmaceutical forms or therapeutic systems which makeretarded and/or controlled release of active ingredient possible areparticularly suitable.

It is particularly advantageous to add one or more antioxidants, such asthose selected from the group consisting of tocopherol and itsderivatives (especially esters, acetate), ascorbic acid and itsderivatives (e.g. ascorbyl palmitate), butyl hydroxyanisol, butylhydroxytoluene and propyl gallate, particularly α-tocopherol andascorbyl palmitate. These substances are added in a concentration of0.01 to approx. 1.0%-wt., or even 0.05 to 0.5%-wt., in each caserelative to the entire pharmaceutical preparation.

The medicaments of the invention comprise 0.1 to 100 mg, particularly0.5 to 20 mg, of compound (1) (or of an active agent according toformula (2)). In the case of oral single-dose forms, the activeingredient content is in the range from 0.1 to 10 mg, and in the case ofdepot pharmaceutical forms or therapeutic systems it is in the rangefrom 1.0 to 100 mg. The content of the other active ingredient/activeingredients mentioned (such as tropane alkaloids) is in the range from0.1 to 100 mg, particularly 0.5 to 50 mg. The percentage of activeingredient, relative to an individual pharmaceutical preparation, is inthe range from 0.1 to 50%-wt., particularly in the range from 5 to40%-wt.

The maximum daily dose (relative to the compound (1)) is approx. 2×6 mgper day (orally) or approx. 24 mg per day (transdermally).

According to one embodiment, the active agent(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate(“compound (1)”), particularly in combination with at least one furtheractive ingredient (especially scopolamine), is contained in a flat,film-like oral administration form. These administration forms, whichare also known under the designation of “wafers”, are intended forapplication in the oral cavity. The medicament, with its active andinactive ingredients adopts a gel-like consistency upon access ofsaliva—or of another liquid—and thereby adheres to the oral mucosa,where the active agents are released and subsequently absorbed via theoral mucosa. During release, the wafer remains in the oral cavity, isvirtually disintegrated and releases the active agent within a veryshort time.

In an alternative administration form, the wafer is provided with anadhesive layer, so that it adheres to the oral mucosa for a controlled,extended period of time.

Wafers substantially contain one or more polymers as base substances, aswell as one or more active ingredient(s) which is/are dissolved ordispersed therein. Suitable polymers are, in particular, water-solublepolymers or polymers which are swellable or disintegratable in aqueousmedia. Particularly suitable are polymers selected from the followinggroup: cellulose derivatives (such as hydroxypropyl methyl cellulose,carboxymethyl cellulose, hydroxypropyl cellulose and methyl cellulose);water-soluble polysaccharides of vegetable or microbial origin (such aspullulan, xanthan, alginates, dextranes, pectins, starch); polyvinylalcohols, polyacrylates, polyvinyl pyrrolidone; proteins (such asgelatine or other gel-forming proteins).

Furthermore, the wafers may contain one or more additives, selected fromthe group of plasticizers, dyes and pigments, antioxidants,disintegration-promoting agents, wetting agents, absorption orpermeation-promoting substances, pH regulators, filling agents,flavorings and aromatics, and sweeteners. Substances which are suitablefor this purpose and which are pharmaceutically acceptable are known tothe skilled person, the same applies to methods of production of suchwafers (see e.g. DE-A-196 52 268; DE-A-100 32 456; WO-A-98 26 763). Inthe production of these wafers, a dispersion or solution of thecomponents (polymer(s), active agent(s), additive(s)) is generallyprepared first, and this is subsequently coated to a flat, inertcarrier.

The thickness of these film-shaped administration forms is between 0.1to 5 mm, or even between 0.5 to 1 mm.

An additional embodiment of the invention provides for the activesubstance or, particularly, an active substance combination as describedabove to be contained in a transdermal therapeutic system (TTS). Sincecompound (1) (as free base or as acid addition salt) as well as, forexample, scopolamine have been shown to be able to penetrate the skin,these substances are suitable for the transdermal administration route.

Transdermal pharmaceutical forms are particularly advantageous for theprophylactic use of phenyl carbamate agents according to the presentinvention because they make precise control of active ingredientdelivery possible over a prolonged period (up to 72 h), with the resultthat the dosage interval can be extended. In this manner it is possibleto maintain a plasma concentration which is sufficient for the desiredprophylactic effect without the occurrence of unfavourable peak plasmavalues or variations in the plasma concentration. For this reason,transdermal administration is also considerably more favourable inrelation to the occurrence of side effects; in a few cases, the peopletreated by oral administration of compound (1) may experience nausea.The risk of overdosage is very substantially precluded with TTS; inaddition, improved acceptance by the people to be treated can beexpected.

The structure and the production of transdermal therapeutic systems(TTS) are in principle known to the skilled person. These systemscomprise an active ingredient reservoir which may be either amembrane-enclosed, bag-like reservoir or a polymer-based reservoir(“matrix system”). The reservoir is normally connected to a supportlayer (e.g. plastic film such as PETP, PE; thickness 10-15 μm, forexample) which serves as a backing layer during application and coversthe active ingredient-containing reservoir toward the outside. The areaof the active ingredient reservoir which faces the skin (delivery side)can optionally be covered before application with a detachableprotective film (e.g. PE or PETP film, siliconized or fluorosiliconized;thickness, for example, 50-250 μm).

Polymers suitable for producing the active ingredient reservoir are, inparticular, polymers from the following groups: polyacrylates,poly(meth)acrylates, polyacrylic acid, cellulose derivatives, inparticular methyl- and ethyl celluloses, isobutylene, ethylene-vinylacetate, natural and synthetic rubbers such as styrene-diene copolymers,styrene-butadiene block copolymers, isoprene block copolymers,acrylonitrile-butadiene rubber, butyl rubber or neoprene rubber,silicone pressure-sensitive adhesives and hot melt adhesives. Suitablepressure-sensitive adhesives are known to those skilled in the art (e.g.amine-resistant silicone pressure sensitive adhesives such as BIO-PSA®pressure sensitive adhesive, especially Q7-4302; Dow Corning). It isalso possible and advantageous to use suitable mixtures of saidpolymers.

The term “hot melt adhesive” encompasses all adhesives which areliquefied not by solvents but by melting at elevated temperatures, forexample in the range 60-200° C. Examples of suitable hot melt adhesivesare mixtures of esters of hydrogenated colophony with cellulosederivatives.

The active ingredient reservoir of the TTS of the invention may furthercomprise various auxiliaries or additives, for example from the group ofsolubilizers, solvents, plasticizers, tackifiers, permeation-improvingagents, pH regulators, antioxidants and preservatives. The polymermatrix of the active ingredient reservoir may be monolayer ormultilayer; but having pressure-sensitive adhesive properties whichenables a lasting contact of the active agent-releasing side of thereservoir to the skin. Alternatively, a separate active agent-freepressure-sensitive adhesive layer or a pressure-sensitive adhesive zonemay be provided if the active ingredient reservoir has no orinsufficient pressure-sensitive adhesive properties.

The typical structure of a TTS according to a preferred one embodimentencloses: a backing layer;(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (asbase or as hydrogen tartrate) in an acrylate copolymer as activeingredient reservoir; silicone pressure-sensitive adhesive layer(BIO-PSA® Q7-4302); detachable protective layer.

As plasticizers, the substances from the following group are taken intoconsideration: eudermic tensides; polyoxyethylene fatty alcohol ethers,such as C₁₂-C₁₈ alcohol, especially polyoxyethylene(10) oleyl ether,especially Brij® 97 (Atlas Chemie); polyoxyethylene sorbitan fatty acidesters, preferably with C₁₂-C₁₈ fatty acids, especially preferablypolyoxyethylene(20) sorbitan mono-oleate (e.g. Tween® 80 (Atlas Chemie);polyoxyethylene-(5-40) stearic acid esters (e.g. Myrj®; Atlas Chemie);polyoxyethylene glycol fatty alcohol ethers, e.g. polyethyleneglycol(6-25)-cetyl ether, glycerol polyethylene ricinoleate; glycerolpolyethylene glycol stearate (Cremophor®; BASF); polyoxyethylene glycolin a molecular weight range from 200 to 600 Dalton; Cetiol® HE (Henkel);lower alkyl esters of adipic acid, especially di-n-butyl adipate,diisopropyl adipate; glycerol polyethylene glycol ricinoleate (e.g.Cremophor EL, BASF®; triacetin-(1,2,3); fatty acids, fatty alcohols, ineach case C₁₂-C₁₈.

As permeation-improving agents (enhancers), Azon (1-dodecylazacycloheptan-2-one) or/and DEET (N,N-diethyl-m-toluamide) may beemployed.

The entire constituent amount of plasticizers and permeation-enhancingsubstances may be up to approx. 50%-wt., relative to the activeingredient-containing polymer preparation (active ingredient reservoir).A content of less than 1%-wt. or complete absence of such additives maybe employed.

The procedure for producing the TTS of the invention can be such thatthe compound (1) and/or an active ingredient of formula (2) as well asoptionally further active ingredients is/are converted into a coarse,colloidal or molecular dispersion in a solution of matrix base polymers,and the mixture is coated onto a suitable substrate, for example aplastic film provided with a silicone layer. Examples of solvents whichmay be used are acetone, ethyl acetate or hexane, or solvent mixtures.After drying and evaporation of the solvent portions, the activeingredient-containing matrix layer is covered with another film whichrepresents the later backing layer of the TTS. Individual TTSs areproduced from such a laminate by punching out sheet-like structures inthe desired geometric shape and size. Alternatively, production of theactive ingredient-containing polymer matrix can start from a polymermelt, in which case the active ingredient-containing molten polymer massis extruded in a thin layer onto a support in the form of a film. Theactive ingredient-containing layer is 10 μm to 2 mm, or even 50 μm to0.5 mm. The skin contact area of a TTS may optionally be approx. 1 to 80cm², or even approximately 2 to 20 cm².

If, as provided in the first embodiment, a TTS comprises the activeingredient (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenylcarbamate (“compound (1)”) in combination with at least one other activeingredient (such as from the group of the tropane alkaloids,particularly scopolamine), it is possible to make use of the measure ofconstructing the TTS from a plurality of layers, surface areas, sectionsor compartments, in which case the individual layers, surface areas,sections or compartments differ through the nature or/and concentrationof the active ingredient present.

A TTS according to one embodiment may, for example, contain twocompartments which serve as a reservoir for the phenyl carbamate agent(compound (1) or/and compound according to formula (2)) and forscopolamine, respectively. These two reservoirs are connected with ashared backing layer and protective layer. The relative surface areadimensions of the two compartments (and/or the relative amounts andconcentrations of the active agents) can be adapted correspondingly inorder to adjust the permeation rate of each one of the active agents.Thus, the first compartment (with a content of compound (1), e.g. 60 mg)may, for example, have an area of 25 cm²; in this case the secondcompartment (with scopolamine; e.g. 4 mg) has an area of 7.5 cm².

As mentioned above, the present invention also comprises TTSs which areconfigured as bag-like systems. In this case the active ingredient(s)is/are contained in a liquid or semi-liquid (e.g. gel-like or viscous)composition which is enclosed in a bag-shaped container. The release ofactive ingredient takes place via an adhesively coated membrane of thecontainer, which membrane comes into contact with the skin of the personto be treated. Suitable materials and methods for producing such systemsare in principle known to those skilled in the art.

Transdermal systems which are particularly advantageously suitable forthe prophylactic administration of compound (1) or active ingredientsaccording to formula (2), possibly in combination with at least onefurther active ingredient, are disclosed in WO-A-99 34782. In thecontext of the present invention, express reference is therefore made tothe pharmaceutical compositions and components described in WO-A-9934782.

In accordance with WO-A-99 34782 the active ingredient(s) is/aredissolved in one or more matrix polymers, such as hydrophile polymers.These polymers are selected from the group of the polyacrylates andpolymethacrylates; their mean molecular weight being in the range fromapprox. 50,000 to approx. 300,000 Dalton. These are, in particular,polymers with film-forming properties.

Substances which may come into consideration are acrylate copolymers,e.g. copolymers of butyl acrylate, ethyl hexyl acrylate and vinylacetate. The use of cross-linked polymers of the type mentioned is alsoof particular advantage. Examples of particularly suitable polymers tobe mentioned are Durotak 87-2353, Durotak 387-2051 and Durotak 387-2052(available from: National Starch and Chemical Company). The portion ofthese polymers may be up to 90%-wt, preferably up to 70%-wt., in eachcase relative to the total weight of the active ingredient-containingpreparation.

Substances suitable as hydrophile polymers are, in particular,polyacrylamide and its copolymers, polyvinyl pyrrolidones, polyvinylalcohol and derivatives thereof, vinyl acetate-vinyl alcohol copolymers,ethyl cellulose and other cellulose and starch derivatives. Hydrophilepolyacrylates may be employed; the polyacrylate may be substituted (e.g.a methacrylate), likewise some or all acid groups may be esterified,e.g. with alkyl(C₁ to C₁₀) groups, especially with methyl or ethylgroups. Examples for commercially available polymers of this type are:Plastoid® B (by Röhm, Darmstadt); Eudragit® RS 100 and RL 100 (Röhm);Eudragit® E 100 (Röhm).

Additionally, hydrophobic polymers may be contained, especially one ormore synthetic resins, possibly in combination with modified substancessuch as colophonic acids, glyceryl esters and phthalate esters ofcolophonic acids.

TTSs with an active ingredient reservoir which has the followingcomposition: 20 to 40%-wt. of(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (asfree base or as salt, particularly as hydrogen tartrate); 10 to 30%-wt.of polymethacrylate; 40 to 60%-wt. of an acrylate copolymer; 0.05 to0.3%-wt. of □-tocopherol (total: 100%-wt.) may also be employed.

The medicaments of the present invention containing compound (1) or/andat least one active ingredient according to formula (2) areadvantageously suitable for the prophylactic treatment of poisoningcaused by cholinesterase inhibitors, in particular toxic substances ofthe type mentioned at the outset. Cholinesterase inhibitors means ingeneral compounds capable of chemical modification of the active centreof the enzyme, in particular through reaction with hydroxyl groups inthe active centre. These are primarily organophosphorus compounds suchas organic phosphoric acid esters and organic phosphonic acidesters andderivatives thereof in each case. In addition, also suitable inconnection with the present invention are cholinesterase inhibitors fromother substance classes, e.g. carbamates, in particular those used ascrop protection agents (e.g. carbaryl=1-naphthyl N-methyl carbamate).

The prophylactic agents or compositions of the invention can be employedin agriculture or horticulture in order to protect the workers who musthandle the organophosphorus insecticides or fungicides, or who may comeinto contact therewith, from possible poisoning. These prophylacticmedicaments are likewise suitable for protecting people employed forweapon decommissioning work or for decontamination work. The inventionfurther includes the use of(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate or of acompound according to formula (2) for the prophylactic treatment ofsoldiers, police officers and civilians for protection from the combatagents or nerve gases mentioned.

The protective effect reduces the toxicity and improves the chances ofsurvival after exposure to toxic substances. It also increases theprospects of successful post-exposure therapy with an atropine-oximecombination.

The present invention also relates to methods for the prophylactictreatment or pretreatment of people in order to protect them frompoisoning caused by exposure to organophosphorus cholinesteraseinhibitors. These methods are distinguished by comprising at least onestep in which a medicament containing(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate or/andan active ingredient according to formula (2) (in each case possibly inthe form of a pharmaceutically acceptable salt) is administered to aperson. The active ingredient-containing medicaments as described aboveare used in this connection.

Prophylactic administration of medicaments containing at least one ofthe above-mentioned phenyl carbamates is carried out at least one day,and in some circumstances only at least 2 hours, before the expectedexposure to toxic substances, where a predictable event is involved(e.g. handling of insecticides, decontamination work, starting a combatoperation). The protective effect can be maintained by administration ofa plurality of consecutive single doses, such as by administration ofdepot pharmaceutical forms or therapeutic systems (particularly TTS),over a period of several (1 to 7) days up to some weeks.

In an alternative embodiment, at least one medicament which comprises(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate or apharmaceutically acceptable salt of that compound as sole activeingredient is administered in the prophylactic method.

A further alternative embodiment of the prophylactic method provides foradditional administration of one or more other active ingredients fromthe group of the parasympatholytics to the person to be treated, such asactive ingredient(s) from the group of the tropane alkaloids,particularly scopolamine. This combined administration can take placeeither by administration of a medicament which comprises said activeingredients in combination, or by simultaneous or successiveadministration of individual medicaments each of which comprises onlyone active ingredient of the combination of active ingredients. Forexample, prophylactic treatment of a person is possible by applicationof a TTS containing(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate to theskin (e.g. the upper arm) and during this application time, oraladministration of a second medicament, which preferably comprisesscopolamine, to this person. An alternative possibility is treatment byapplication of a TTS which comprises a combination of at least twoactive ingredients (e.g.(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate andscopolamine) to the skin. There is also provision further forcombination of transdermal or oral administration of(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate withparenteral administration of at least one further active ingredient,such as from the group of parasympatholytics.

In the case of transdermal administration of the active ingredients (asdescribed above), the protective effect occurs after approx. 4 h at theearliest. This delay can in certain circumstances be critical, e.g. inthe case of a terrorist attack, where immediate intervention by soldiersor police is required. To achieve an earlier onset of protective action,the present invention includes a method for prophylactic treatment whichcombines transdermal administration and oral administration of theabove-mentioned active ingredients. In a first step,(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (or acombination of that active substance and scopolamine) is administeredvia the oral route to a person for whom a quick onset of the protectiveeffect is required. In this manner it is possible to achieve therapeuticplasma levels within a short period of time (within approx. ½ h) whichoffer protection from combat agents. This enables the treated person toaccess a contaminated area immediately after receiving the emergencydeployment order.

In a second step, a transdermal system (as described above) isadministered to the same person in order to achieve a lasting protectiveeffect (e.g. up to 24 hours). Application of the TTS may take place atthe same time as administration of the oral medicament; it may, however,also be carried out after a delay in time, such as within 12 hours afteroral administration. This second step may be repeated in certain timeintervals (e.g. 6 to 24 hours) to prolong protective action. Accordingto this method, oral administration is necessary only in order toachieve an early onset of protective action; maintaining the protectiveeffect is made possible by administering one or more transdermaltherapeutic systems. This method is particularly uncomplicated and safein handling; it enables a quick build-up of a prophylactic protectiveeffect in the persons to be protected without subjecting those personsto unacceptable stress caused by side effects.

Oral administration forms for use in the methods described above aretablets and, particularly, “wafers” (film-like or wafer-likeadministration forms; as described above). According to one embodimentof the process, a wafer containing compound (1) and scopolamine isapplied into the oral cavity of a person. The active substances arereleased from the wafer and absorbed via the oral mucosa. A therapeutic,prophylactic plasma level that ensures a protective effect is quicklyachieved (e.g. within 30 min).

The prophylactic agents/compositions and methods of the invention areadvantageously suitable for the pretreatment of people at risk ofexposure to toxic substances.

EXAMPLE

To show the prophylactic property of the combination of(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate(compound (1)) and scopolamine against nerve poisons, the protectiveaction was examined in a study on piglets as an animal model. The plasmalevels of the two active ingredients were adjusted in the animals so asto be within a range corresponding to that which is to be used inhumans.

In a preliminary test, 6 mg(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamatehydrogen tartrate was administered to the piglets (12 kg each) orally inthe form of capsules. This caused a 20-40% inhibition of the enzymecholinesterase in the blood two hours after administration. This rangecorresponds to the inhibition which is aimed at and is to be achieved inhumans. In this context, it has to be taken into consideration that inhumans a lower dose is required on account of the better absorption ofthe active agent. Based on the blood cholinesterase inhibition measuredin humans it can be assumed that a treatment with 3 mg BID (i.e. twicedaily) is sufficient to ensure the necessary protective effect. Thisdose is thus considerably smaller than the dose employed for treatmentof Alzheimer patients (12 mg per day; Culter N R et al.: Dose-dependentCSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer'sdisease. Acta Neurol. Scand., 1998, 97, 244-250).

In a further preliminary experiment, it has emerged that intravenousinfusion of scopolamine at a rate of 0.8 mg/kg/h leads to an equilibriumconcentration of approx. 150 pg/ml in the piglets' blood; here, too,this value corresponds to the concentration which according toexpectation is to be achieved in humans.

In the experiments on protective effect, the piglets were subjected to adose of the nerve combat agent sarin which corresponded to double theLD₅₀ dose (40 μg/kg); this was done by means of an intravenous cannulain an ear of the piglets. Untreated piglets (control) died within 4 to 6minutes after exposure to the combat agent. Treated piglets (eachapprox. 12 kg) were administered a 6 mg capsule(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamatehydrogen tartrate; in addition, the piglets were infused withscopolamine (0.8 mg/kg/h) 2 hours prior to exposure. Before treatmentwith active agent and immediately before exposure, blood samples weretaken from the Vena subclavia to determine scopolamine and to assesscholinesterase inhibition.

As can be seen from the following table, all five piglets survived.Furthermore, the average recovery time, during which the piglets werestanding firmly on their feet, was extraordinarily short (17 min)despite the relatively high dose of nerve combat agent. TABLE Protectionof pigs from sarin (2 × LD₅₀) by prophylactic treatment with(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamatehydrogen tartrate (orally) and scopolamine (infusion) Surviving Averagerecovery Average ChE Average scopol. conc. animals time [min.] inhibtion[%] [pg/ml] 5/5 17 28 240ChE = Cholinesterase

What has been described above are preferred aspects of the presentinvention. It is of course not possible to describe every conceivablecombination of components or methodologies for purposes of describingthe present invention, but one of ordinary skill in the art willrecognize that many further combinations and permutations of the presentinvention are possible. Accordingly, the present invention is intendedto embrace all such alterations, combinations, modifications, andvariations that fall within the spirit and scope of the appended claims.

1.-24. (canceled)
 25. A medicament for the prophylaxis of poisoning bycholinesterase inhibitors, containing at least one active ingredientaccording to the following formula (2)

wherein, R₁ is selected from the group consisting of hydrogen,straight-chain and branched lower alkyl residues (1 to 5 C atoms),cyclohexyl, allyl and benzyl; R₂ is selected from the group consistingof hydrogen, methyl, ethyl and propyl; R₃ is selected from the groupconsisting of hydrogen and straight-chain and branched lower alkylresidues (1 to 5 C atoms); wherein said residues R₄ and R₅ are selectedfrom the group consisting of straight-chain and branched lower alkylresidues (1 to 5 C atoms), said R₄ and R₅ being identical or different;and wherein the dialkyl aminoalkyl group with the residues R₃, R₄ and R₅being in a position selected from the group consisting of ortho, metaand para position; said active ingredient being present in a formselected from the group consisting of a free base and a pharmaceuticallyacceptable salt; and wherein said medicament comprises at least oneadditional active ingredient selected from the group consisting ofparasympatholytics.
 26. The medicament according to claim 25 whereinsaid active ingredient comprises(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate havingthe following formula (1)


27. The medicament according to claim 25, wherein said at least oneactive ingredient according to formula (2) is present as an acidaddition salt.
 28. The medicament according to claim 27, wherein saidacid addition salt is selected from the group consisting ofhydrochloride and hydrogen tartrate.
 29. The medicament according toclaim 25, wherein said medicament is selected from the group consistingof orally, rectally and transdermally administrable medicaments.
 30. Themedicament according to claim 25, wherein said medicament is present ina form selected from the group consisting of a transdermal therapeuticsystem and a film-like oral dosage form.
 31. The medicament according toclaim 25, wherein said medicament comprises said at least one activeingredient in an amount of 0.1 to 100 mg.
 32. The medicament accordingto claim 25, wherein said at least one additional active ingredient isselected from the group consisting of tropane alkaloids.
 33. Themedicament according to claim 32, wherein said at least one additionalactive ingredient is scopolamine.
 34. A method for the prophylactictreatment of people against poisoning caused by exposure tocholinesterase inhibitors selected from the group consisting oforganophosphorus compounds and carbamates, wherein said method comprisesat least one step of administering a medicament to a person who is to beprotected, said medicament comprising at least one active ingredientaccording to the following formula (2)

in a form selected from the group consisting of a free base and apharmaceutically acceptable salt.
 35. The method according to claim 34wherein said active ingredient comprises(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate havingthe following formula (1)


36. The method according to claim 35, wherein said medicament comprisessaid active ingredient(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (1) asthe sole active ingredient.
 37. The method according to claim 34,wherein said at least one active ingredient according to formula (2) isthe sole active ingredient for prophylaxis.
 38. The method according toclaim 34, further comprising the step of administering to the person tobe treated at least one additional active ingredient selected from thegroup consisting of parasympatholytics.
 39. The method according toclaim 34, further comprising the step of administering to the person tobe treated at least one additional active ingredient by a combinationpreparation containing at least one active ingredient according toformula (2) and at least one active ingredient selected from the groupconsisting of parasympatholytics.
 40. The method according to claim 39,wherein the combination preparation contains the active ingredient(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (1).41. The method according to claim 34, wherein at least one of said atleast one active ingredient is administered in a route selected from thegroup consisting of orally and transdermally.
 42. The method accordingto claim 34, wherein said poisoning is caused by the uptake of at leastone substance selected from the group consisting of organic phosphoricacid esters, organic phosphonic acid esters, derivatives of organicphosphoric acid esters and derivatives of organic phosphonic acidesters.
 43. The method according to claim 34, wherein said poisoning iscaused by crop protection agents.
 44. The method according to claim 34,wherein said poisoning is caused by a poison selected from the groupconsisting of combat agents and nerve gases.
 45. The method according toclaim 41, comprising the steps of: introducing a film-like oraladministration form (wafer) into the oral cavity of a person, oradministering a tablet, pill, capsule or coated tablet to the person;and applying a transdermal therapeutic system to the skin of the person,wherein said medicaments comprise said at least one active ingredientaccording to formula (2), and wherein said at least one activeingredient is present in the form selected from the group consisting ofa free base and a pharmaceutically acceptable salt.
 46. The methodaccording to claim 45 wherein said active ingredient comprises(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate offormula (1).
 47. The method according to claim 45, wherein at least oneof said medicaments administered to the person further comprise at leastone additional active ingredient selected from the group ofparasympatholytics.
 48. The medicament according to claim 47, whereinsaid at least one additional active ingredient is selected from thegroup consisting of tropane alkaloids.
 49. The medicament according toclaim 48, wherein said at least one additional active ingredient isscopolamine.
 50. The method according to claim 47, further comprisingthe step of administering to the person to be treated at least oneadditional active ingredient by a combination preparation containing atleast one active ingredient according to formula (2) and at least oneactive ingredient selected from the group consisting ofparasympatholytics.